臺灣博碩士論文加值系統

細胞中具有對紫外輻射損傷DNA的結合活性主要包含兩種蛋白：受損DNA結合蛋白1 (DDB1) 和2 (DDB2)。為能進一步瞭解這兩種蛋白如何調控其對紫外輻射損傷DNA的結合活性，我們檢查了三種鼠類細胞株的 UVDRP 活性及其DDB1 和 DDB2 的表現，並進而取大鼠不同器官的蛋白分析其UVDRP活性與受損DNA結合蛋白表現的關連性，發現能影響蛋白結合活性的因素除了 DDB1 存在與否外；DDB2同時也扮演增強結合活性的角色。為了進一步證明此推論，我們首先從大鼠 cDNA 庫中選殖出完整的大鼠 ddb1 cDNA，將其核酸序列轉錄成蛋白序列，可預期得到一個分子量 126.8 kDa 的蛋白分子，其蛋白序列與人類及其它物種之DDB1 序列作比較，發現皆有很高的相似性(>98%)；因此推測DDB1在生物體中應具有重要之功能角色。利用DNA病毒載體分別攜帶大鼠ddb1與人類ddb2感染受測細胞，結果顯示單獨表現DDB1不能提升蛋白與損傷DNA的結合活性，但是增加DDB2的表現可明顯提升蛋白與受損DNA的結合活性。然而同時增加兩種蛋白表現卻不能再加強已有的結合活性，顯示DDB2主要參與調控UVDRP的活性。
雖然還不清楚DDB蛋白與損傷DNA結合活性在細胞中之功能，但是已知DDB2發生突變會導致細胞對多種基因毒性物質的敏感性增加；其中包括紫外輻射。因此可推測DDB2在紫外輻射引起的DNA修補機制中扮演一定的角色。但是實際上有關DDB2參與DNA修補與對紫外輻射敏感性的證據仍舊缺乏，為了進一步研究DDB2的功能，我們建立一株可表現DDB2蛋白的倉鼠細胞株V79ddb2。在其修補DNA的效率分析上，發現該細胞株在12小時內可移除近50%的紫外輻射損傷的DNA；但是缺乏DDB2表現的母細胞株卻不具有這樣的修補能力。然而利用CAT基因當作報導基因的修補分析，顯示兩株細胞對紫外輻射損傷DNA的修補並無差異，此結果可推測DDB2可能只參與染色體DNA之修補。另外在紫外輻射引起細胞凋亡與細胞毒性的分析方面，V79ddb2細胞也顯示比母細胞株有抗紫外輻射的能力。
利用抗癌藥順鉑(cisplatin)逐步從人類子宮頸上皮細胞株(HeLa)篩選出的抗藥細胞株(HeLa-CPR)除能抗順鉑外，也同時具有抗紫外輻射的能力，進一步檢測其DDB蛋白的表現顯示DDB1並無差異；但是DDB2 的表現量比起母細胞株卻有明顯的增加。為了進一步探討DDB2在抗紫外輻射的過程中所扮演的角色功能，我們首先利用反向表現的人類ddb2 cDNA從抗藥細胞株中篩選出DDB2表現被壓制的細胞株 HRddb2as，經由紫外輻射的處理顯示因DDB2的表現減少，會導致抗藥細胞抗紫外輻射的能力也隨之降低。分析紫外輻射所引起的細胞凋亡指標，我們發現DDB2表現量的多寡可影響執行凋亡的酵素被活化的程度，也就是說DDB2表現量高時能夠保護細胞減緩紫外輻射所引起之細胞凋亡；反之則會增強細胞的凋亡。由以上這些結果可推測DDBs除可調控對損傷DNA結合活性，並經由DNA結合活性的增加進而增強細胞修補能力，另一方面DDB2可減緩紫外輻射所導致的細胞凋亡作用；而不能與DDB1合作辨識受損DNA的DDB2突變株也可降低紫外輻射引起的細胞凋亡，顯示DDB2的抑制細胞凋亡作用可能與DNA修補無關。整體而言，DDBs在保護細胞免於紫外輻射傷害應是透過多種機制調控的結果。
在順鉑損傷DNA辨識蛋白HMGB1的研究中，抗藥細胞株因HMGB1辨識受損DNA的活性降低而導致細胞修補能力增加，其原因可能是HMGB1會與修補蛋白競爭，遮蔽受損傷的DNA位置使其無法被修補蛋白辨識進而增加了順鉑的細胞毒性。我們的結果則發現在細胞內和細胞外增加HMGB1的磷酸化可降低蛋白與受損DNA的結合，而蛋白的磷酸化可能是透過蛋白激活酵素C (PKC)的作用：HMGB1主要被磷酸化的氨基酸是絲氨酸(serine)；被磷酸化的HMGB1可能是因結構改變而影響蛋白對損傷DNA辨識。從我們的結果中也許可提供一個思考方向，即如何透過對HMGB1的磷酸化調控以增加抗癌藥順鉑的細胞毒性。

Damaged DNA-binding (DDB) activity comprises two major protein components, damaged DNA-binding protein 1 (DDB1) and 2 (DDB2). Those are implicated in the repair of ultraviolet (UV) radiation—induced DNA damage. To assess the functional correlation between DDBs and UV-damaged-DNA recognition activity, we identified UV-damaged-DNA recognition activities in rodent cell lines. There is a cell type-dependent expression of DDB1 and DDB2. Rodent cells had less abundant DDBs and lower UV-damaged-DNA recognition activity than did human tumor cells. Interestingly, the profusion of DDBs is associated with UV-damaged-DNA recognition activity in these rodent cell lines. We also discovered rat tissue-dependent expression of DDBs and its functional correlation with UV-damaged-DNA recognition activity. Moreover, the rat DDB1 cDNA (3850 nucleotides) from rat brain cDNA library was isolated. It contained the complete length of the open reading frame that encodes an 1140-amino-acid polypeptide with a predicted molecular weight of 126.8 kDa. The predicted protein size from the rat ddb1 gene resembles that from human DDB1 (127 kDa). Rat DDB1 shares highly conserved sequencing (greater than 98% similarity) with those of mouse, human, and monkey. Rat and fruit fly DDB1 exhibit 62.23% identity and 57.66% homology, respectively. The evolutionary conservation of the DDB1 sequence suggests that DDB1 may play a pivotal role in mammals as well as in other eukaryotes. However, overexpression of DDB1 through a recombinant rat ddb1 adenovirus did not augment UV-damaged-DNA recognition, whereas overexpressing DDB2 through a recombinant human ddb2 adenovirus partly restored the recognition activity of rodent cells.
To examine the DDB2-modulated DDB activity involving in DNA repair and UV sensitivity, we established DDB2-overexpressing hamster V79 cell line that was stable transfectted with full-length open reading frame of human ddb2 cDNA. DDB activity was increased in DDB2-overexpressing cell lines. Analysis on DNA repair indicated that UV photoproducts were removed in a time-dependent manner and there was greater than 50% of damage removed within 12 h in DDB2-overexpressing cells. In contrast, nearly all the damage remained unrepaired in V79 cells. However, using bacterial CAT gene as a reporter, both parent and DDB2-overwxpressing cells demonstrated no difference in the reactivation of plasmid DNA carrying UV damage. These results suggest that DDB2 may proficiently involve in repair of bulky genomic DNA damage. DDB2-overexpressing cells also displayed resistance to UV-induced apoptosis and cytotoxicity. Moreover, the possible role of DDB2 as a determinant of cellular sensitivity to UV was investigated. DDB2-depleted cells were established by stable transfection of the resistant cells with DDB2 antisense cDNA. The cells that have depletion of DDB2 protein can restore cellular sensitivity to UV-induced apoptosis. Whereas the extent of UV-induced activation of apoptosis executioners, including DNA fragmentation factor, and caspase-3 were reduced in the UV-resistant cells compared with those apparent in the sensitive cells, depletion of DDB2 from the resistant cells restored the normal activation patterns for these proteins. Our findings indicate that DDB2 potentiates DNA repair and protects cells from UV-induced cytotoxicity and apoptosis. These results also suggest that DDB2 involved in the development of UV resistance.
In cisplatin-damaged DNA recognition protein study, we found that high mobility group binding protein 1 (HMGB1) DRP activity was reduced with the extent of cell resistance to cisplatin. Induction of PKC activity by TPA lowered DRP activity of HMGB1 both in sensitive and resistant cells. However, inhibition of PKC activity by sphingosine or staurosporine failed to decrease HMGB1 activity in both cells. The result indicates a possible mechanism, through the phosphorylated HMGB1 reduce its damaged DNA DRP activity that resulted in cells proficient to resistant cisplatin.

Contents
Chapter 1 ……………………………………………………..…………………… 2
Introduction - Cell response to DNA damage
I. Cell response to UV damage ………………………….…………… 4
II. Cell response to cisplatin damage ……………………………...... 17
III. The multiple roles of DRPs ……………………………………… 36
Chapter 2 ………………………………………………………………………. 41
Analysis of mammalian DDB, a putative repair protein, and function correlation with its damaged-DNA recognition activity
Chapter 3 …………………………………………………………….…………. 64
Overexpression of damaged DNA-binding protein 2 (DDB2) potentiates DNA repair and apoptotic resistance in UV-treated cells
Chapter 4 ………….…………………………………………………………..... 79
Restoration of UV sensitivity in UV-resistant cells by antisense-
mediated depletion of damaged DNA-binding protein 2 (DDB2)
Chapter 5 …………………………………………………………………………. 93
PKC-dependent HMG1 phosphorylation reduces damaged-DNA
recognition that is associated with cellular resistance to cisplatin
Conclusion ………….…………………………………………………………. 114
References ……………………………………………………………………...… 115
Appendix ………………………………………………………………..………. 143

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